Role of fibrillin-1 in protecting against osteoarthritis.

fibrillin-1 在预防骨关节炎中的作用。

• 批准号: MR/X021068/1
• 负责人: Blandine Poulet
• 金额: $ 115.08万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX021068%2F1
• 关键词: Role; fibrillin; protecting; against; osteoarthritis.

ImportanceOsteoarthritis is the most common form of arthritis in the UK. It causes joints to become painful and stiff and although symptoms can be mild for some people, for others the pain and mobility issues prevent everyday activities. In the UK osteoarthritis in the knee alone affects 18% of people aged over 45 years. The proportion of the UK population in this age group is growing, and it is predicted that that UK care costs for arthritic conditions will grow to £120 billion per year by 2030. Osteoarthritis is a degenerative condition - one which gets worse over time - and there is currently no drug that can slow or stop osteoarthritis from getting worse.Our goalsThe protein fibrillin-1 (FBN1) is a key component of the network that forms the structure of tissues such as ligaments and bones. We recently discovered that FBN1 may play an important role in osteoarthritis. In addition to other groups' findings that FBN1 levels change in human osteoarthritis, we also found that mice with an abnormal FBN1 protein had early onset osteoarthritis, which was particularly severe in male mice. These findings support a sex-dependent role for FBN1 in osteoarthritis, with FBN1 being critical for avoiding joint failure. In this project we aim to - Define whether loss of FBN1 makes osteoarthritis get worse once it has been triggered or makes joints more susceptible to initial damage in the first place. - Determine the mechanism by which FBN1 causes osteoarthritis. - Test whether preventing FBN1 from breaking down can protect joints from worsening osteoarthritis.Our approachWe have created a team with the range of skills needed to fully understand the role of FBN1 in osteoarthritis, including expertise in the biology of osteoarthritis progression, ligament biology and strength measurements in humans and animals using a mixed engineering and biological approach, creating and using mouse models to understand osteoarthritis and protein breakdown. We will generate mouse strains where FBN1 is deleted in whole limbs or just part of the joint, and also with a variant of FBN1 that is more difficult to break down than the usual form. The mice will be analysed over several months looking at their walking gait, general behaviour, and images of their joints to understand how lack of FBN1/lack of FBN1 breakdown affects joint health and function. We will also use human samples to investigate the mechanism of FBN1 action at a cellular level. ImpactTogether, our experiments will: - determine whether FBN1 controls progression of osteoarthritis only, or whether it also plays a role in initiation. This information is important to determine the timing for treatment targeting FBN1. - unravel the mechanisms by which FBN1 loss accelerates osteoarthritis, and therefore reveal potential targets for therapy. - discover whether preventing FBN1 from breaking down is a valid potential strategy for slowing progression of osteoarthritis.Our work will deliver new scientific insights into the role of FBN1 in osteoarthritis. This paves the way for future work developing new therapies against this increasingly important disease.

骨关节炎是英国最常见的关节炎。它会导致关节疼痛和僵硬，虽然对某些人来说症状可能很轻微，但对其他人来说，疼痛和流动性问题会阻止日常活动。在英国，仅膝关节骨关节炎就影响了45岁以上人群的18%。这个年龄组的英国人口比例正在增长，据预测，到2030年，英国关节炎疾病的护理费用将增长到每年1200亿英镑。骨关节炎是一种退行性疾病，会随着时间的推移而恶化，目前还没有药物可以减缓或阻止骨关节炎的恶化。我们的目标蛋白质FBN 1是形成韧带和骨骼等组织结构的网络的关键组成部分。我们最近发现FBN 1可能在骨关节炎中发挥重要作用。除了其他研究小组发现FBN 1水平在人类骨关节炎中发生变化外，我们还发现FBN 1蛋白异常的小鼠患有早发性骨关节炎，这在雄性小鼠中尤为严重。这些发现支持FBN 1在骨关节炎中的性别依赖性作用，FBN 1对于避免关节衰竭至关重要。在这个项目中，我们的目标是-定义FBN 1的丢失是否会使骨关节炎变得更糟，一旦它被触发或使关节更容易受到初始损伤摆在首位。- 确定FBN 1导致骨关节炎的机制。- 测试阻止FBN 1分解是否可以保护关节免受骨关节炎恶化。我们的方法我们已经创建了一个团队，该团队具有充分了解FBN 1在骨关节炎中的作用所需的一系列技能，包括骨关节炎进展生物学，韧带生物学以及使用混合工程和生物学方法测量人类和动物强度的专业知识，创建和使用小鼠模型来了解骨关节炎和蛋白质分解。我们将生成FBN 1在整个肢体或仅部分关节中缺失的小鼠品系，并且还具有比通常形式更难分解的FBN 1变体。研究人员将在几个月内分析小鼠的行走步态、一般行为和关节图像，以了解缺乏FBN 1/缺乏FBN 1分解如何影响关节健康和功能。我们还将使用人体样本来研究FBN 1在细胞水平上的作用机制。总之，我们的实验将：-确定FBN 1是否仅控制骨关节炎的进展，或者它是否也在启动中起作用。该信息对于确定靶向FBN 1的治疗时机非常重要。- 揭示FBN 1缺失加速骨关节炎的机制，从而揭示潜在的治疗靶点。- 发现阻止FBN 1分解是否是减缓骨关节炎进展的有效潜在策略。我们的工作将为FBN 1在骨关节炎中的作用提供新的科学见解。这为未来开发针对这种日益重要的疾病的新疗法铺平了道路。